IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18
Open Access
- 27 September 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (41), 17680-17685
- https://doi.org/10.1073/pnas.1012977107
Abstract
IκBζ, encoded by Nfibiz, is a nuclear IκB-like protein harboring ankyrin repeats. IκBζ has been shown to regulate IL-6 production in macrophages and Th17 development in T cells. However, the role of IκBζ in natural killer (NK) cells has not be understood. In the present study, we found that the expression of IκBζ was rapidly induced in response to IL-18 in NK cells, but not in T cells. Analysis of Nfkbiz−/− mice revealed that IκBζ was essential for the production of IFN-γ production and cytotoxic activity in NK cells in response to IL-12 and/or IL-18 stimulation. IL-12/IL-18–mediated gene induction was profoundly impaired in Nfkbiz−/− NK cells. Whereas the phosphorylation of STAT4 was normally induced by IL-12 stimulation, STAT4 was not recruited to the Ifng gene regions in Nfkbiz−/− NK cells. Acetylation of histone 3 K9 on Ifng regions was also abrogated in Nfkbiz−/− NK cells. IκBζ was recruited on the proximal promoter region of the Ifng gene, and overexpression of IκBζ together with IL-12 activated the Ifng promoter. Furthermore, Nfkbiz−/− mice were highly susceptible to mouse MCMV infection. Taken together, these results demonstrate that IκBζ is essential for the activation of NK cells and antiviral host defense responses.Keywords
This publication has 35 references indexed in Scilit:
- Modular Utilization of Distal cis-Regulatory Elements Controls Ifng Gene Expression in T Cells Activated by Distinct StimuliImmunity, 2010
- Pattern Recognition Receptors and InflammationCell, 2010
- Nuclear protein IκB-ζ inhibits the activity of STAT3Biochemical and Biophysical Research Communications, 2009
- A Novel Role for IκBζ in the Regulation of IFNγ ProductionPLOS ONE, 2009
- In vitro and in vivo differentiated effector CD8 T cells display divergent histone acetylation patterns within the Ifng locusImmunology Letters, 2009
- Epigenetics and T helper 1 differentiationImmunology, 2009
- Class-specific Regulation of Pro-inflammatory Genes by MyD88 Pathways and IκBζJournal of Biological Chemistry, 2008
- Evolutionary struggles between NK cells and virusesNature Reviews Immunology, 2008
- Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activationBiochemical Journal, 2007
- NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate CytokinesAnnual Review of Immunology, 1999